1. ABSTRACT/SUMMARY Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure in which the life of expectancy of affected children is severely truncated. Treatment of PDCD remains a serious, unmet, challenge. There has never been a controlled trial of any intervention for PDCD; thus, there is no proven therapy for affected patients. Dichloroacetate (DCA) represents the first targeted therapy for PDCD by stimulating residual PDC activity in all tissues, including the central nervous system (CNS). Based on both controlled trials and open label studies of DCA in mitochondrial diseases, Medosome Biotec, LLC (MBT) and its research partners at the University of Florida (UF) (Drs. Peter Stacpoole and Taimour Langaee, PD/PIs for Phase I) determined the data were sufficiently compelling to justify a pivotal phase 3 trial of DCA in this disease, for which Dr. Stacpoole at UF and Dr. J.L.P. Thompson at Columbia University are PD/PIs. In response to these promising studies and extensive potential commercial market, Medosome Biotec, LLC (MBT) and its research partners at UF have developed a central STTR hypothesis that GSTZ1 haplotype- based dosing of DCA has the potential to provide safe and effective treatment for PDCD and other diseases for which DCA may be beneficial. The team proposes a STTR Fast Track to test this. Phase I: Develop a procedure for GSTZ1 haplotypes analysis (referred to as Halotype Identification Procedure or HIP) that can be used by physicians for personalized dosing of DCA. Phase I Specific Aim: 1) Establish the accuracy and validity of the GSTZ1 haplotype analysis by determining the plasma pharmacokinetics (PK) of DCA in subjects identified in Specific Aim 2 who are predicted to be slow or fast DCA metabolizers, based on GSTZ1 haplotype analysis. Phase II: Use the new procedure to accurately genotype and dose-stratify PDCD patients for the Phase 3 trial. The team will test these hypotheses by accomplishing the following Phase II Specific Aims: 1) Conduct a pivotal Phase 3 trial, consistent with FDA guidelines, that could lead to the agency's approval of DCA for PDCD, using the procedure developed during Phase I to provide personalized, genetics-based dosing to improve the safety of chronic DCA treatment; and 2) Commercialize the kit and analytic procedures for use in PDCD and other diseases amenable to DCA treatment.